Strong structuring arising from weak cooperative O-H···π and C-H···O hydrogen bonding in benzene-methanol solution

Weak hydrogen bonds, such as O-H···π and C-H···O, are thought to direct biochemical assembly, molecular recognition, and chemical selectivity but are seldom observed in solution. We have used neutron diffraction combined with H/D isotopic substitution to obtain a detailed spatial and orientational picture of the structure of benzene-methanol mixtures. Our analysis reveals that methanol fully solvates and surrounds each benzene molecule. The expected O-H···π interaction is highly localised and directional, with the methanol hydroxyl bond aligned normal to the aromatic plane and the hydrogen at a distance of 2.30 Å from the ring centroid. Simultaneously, the tendency of methanol to form chain and cyclic motifs in the bulk liquid is manifest in a highly templated solvation structure in the plane of the ring. The methanol molecules surround the benzene so that the O-H bonds are coplanar with the aromatic ring while the oxygens interact with C-H groups through simultaneous bifurcated hydrogen bonds. This demonstrates that weak hydrogen bonding can modulate existing stronger interactions to give rise to highly ordered cooperative structural motifs that persist in the liquid phase.

The authors present an interesting study on benzene-methanol correlations in a binary solution using neutron scattering with isotope substitution to locate methanol protons correlated with benzene in a binary solution.The manuscript reports on a very specific structuring of methanol about a benzene (Figure 3).Whereas the neutron data are interesting, they do not appear to support the conclusions, which appear to be largely derived from modeling.Specifically: There are two OH-methanol shown orthogonal to the benzene ring (Figure 3a2).It does not appear that there are peaks at 6.2 Å (H-H) or 7.4 Å (O-O) in the experimental data to support two correlated methanol to one benzene.The text discusses this point but it is not made clear that the data do not provide the information necessary to distinguish one associated H-O from two.The comment (line 107) that the two faces act independently with no probabilistic preference is questionable based on a wide range of precedent and no justification is made for this assertion.Absent assignable H-H or O-O peaks in the data this conclusion is not justified.
There are no clearly discernible correlation peaks in the experimental data beyond about 3 Å (Figure 1) raising concern about the degree to which the results are dependent on the neutron data.The data do not correspond to the calculated partial RDFs shown in the SI, notably at the longer distances.
The Figure 3 caption states confidence in the model as, for example, "5% most likely position".What exactly does this mean?
The relative concentration of benzene/methanol used in the neutron experiments is not explicitly stated although a 1:19 ratio is referenced in several SI figure captions.Benzene/methanol have a wide miscibility range.Whatever the single concentration used for all the scattering studies, it needs to be provided in the main text along with the rationale for this choice.There is also no discussion about the relevance of the structure determined at this one specific ratio to the wider miscibility region.Since the experiments were obtained at a single ratio there is no evidence for the transferability of the structure seen at this specific ratio to the extended benzene/methanol phase space.
Overall, the broad conclusions presented in this manuscript are not supported by the data presented.The finding of methanol proton centered in the benzene pi-cloud, with a H-O bond perpendicular to the benzene plane appears to be a defensible result that may be appropriately published in a more specialized journal.

Reviewer #3 (Remarks to the Author):
This is a nice study of weak hydrogen bonds using unique capabilities at the ISIS facility, measuring neutron diffraction, comparing H and D substituted molecular systems.This measurement provides detailed insight into spatial and orientational correlations.The results provide an important benchmark to molecular simulations as well as a qualitative understanding of competing molecular interactions, be it O-H ... pi or C-H ... O, dipole interactions, or dispersion interactions.The incremental complexity of the miscible binary system of benzene in methanol is significant and relevant.
Reviewer #4 (Remarks to the Author): This publication presents an original neutron diffraction study on the benzene-methanol binary mixture, extended by Monte Carlo simulations.The intramolecular orientation of both solvent partners in the liquid is explained presenting their cooperative effect.The paper shows for the first time the high directionality of the O-H...pi bond toward the center of the pi-ring and the highly equatorial structure of the C-H...O bonds relative to benzene.
This study is novel work with a high significance to the field of molecular liquids and binary mixtures.This will give a enhanced insight in weak interactions of the title bonding.The detailed analysis and results are clearly described to guide the reader to this interesting conclusions.
Recommendation: accept with minor changes.

Minor points:
-The authors should give the experimental 1:19 benzene-methanol molar ratio also in the main manuscript.
-The conclusion that 51% probability for zero and 41% for one methanol molecule in the axial position of the pi-face is correlated with the fact that CoM...H-O is a weak interaction (line 105 on p.5), is not clear without defining criteria for a weak bond.This fact could be supported by the information how much methanol molecules surround one benzene molecule on average and in this position.
-From Fig. S5 it is visible that the benzene-benzene distance stays the same for the first solvation shell, but the second solvation shell is contracted upon addition of methanol.This is an important fact, also for the conclusion.
-Can the authors extract the information, how the benzene molecules are located relative to each other (only the distance of ca.5.5 Angstrom is visible from Fig. S5), the ARDFs could help interpreting, how methanol is located between two benzene molecules.
-The structures in Fig. 2 are difficult to interpret inside the figure.I suggest to add them aside the graph with additional markings of the distances.

Reviewer #1 (Remarks to the Author):
This paper presents a detailed study of the interactions of methanol with benzene at a ratio of 50 benzene to 950 methanol molecules to determine the existence of possible hydrogen-pi bonding interactions in the liquid state.This is an interesting question which is difficult to probe by spectroscopic techniques, and where computational studies have proposed several possible minimum energy configurations for such weak hydrogen bonds.The scattering study has been performed using a standard methodology and provides an impressive number of experimental data sets to constrain the monte carlo modeling used to fit the data.This study provides experimental evidence for two dominant non-covalent interactions between the methanol OH group and the benzene pi system which may help explain reactivity and solubility in this and other systems containing such weak hydrogen bonds.Interestingly standard simulation methods used by the authors on the same system do not pick up the interactions seen in the experimental study, so underestimate important contributions to the liquid structure.The work will therefore be of interest not only to computational chemists but also to those interested in extractions, separations, and reactivity in mixed solvents.

Author reply:
• We thank the referee for their evaluation of our work and recommendation.

The authors should just clarify a couple of points in their work before publication to assist understanding of their paper.
Was there a reason for picking 50 benzene to 950 methanol or is this just a convenient ratio where the benzene molecules should each be fully solvated by methanol?

Author reply:
• As the referee has noted in their summary, the primary aim of this work is to study weak interactions between methanol and benzene.Hence, we did indeed investigate a ratio (1:19) where each benzene molecule should be well solvated by methanol.In addition, at this concentration the neutron scattering contributions from benzene are measurable and the data therefore allows us to probe, for example, subtle intermolecular OH•••π and CH•••O hydrogen bonds.
We chose a molecular composition of 50 benzene and 950 methanol (1:19 ratio) for our EPSR modelling of the data as this system has a cubic box side of 41.95 Å and is therefore sufficiently large to capture possible solute-solute, solute-solvent and solvent-solvent intermolecular interactions.

Suggested changes to the manuscript:
• We have added explanatory text on page 4 lines 41 -45: "Benzene-methanol solutions have been studied as a function of isotopic composition at a molecular ratio of 1 benzene for every 19 methanol molecules (0.05 mole fraction benzene).At this level of dilution, the solvation of benzene is dominated by interactions with methanol while still providing a measurable contribution to the experimental neutron scattering signal (see Supporting Information Table S1).This allows us to probe subtle intermolecular interactions, including benzene-methanol OH•••π and CH•••O hydrogen bonds." • We have added explanatory text on page S4 lines 87 -89: "This model of the system reproduces the experimental composition and density and is sufficiently large to capture possible solute-solute, solute-solvent and solventsolvent intermolecular interactions".
There is a comment in Figure S2 caption which suggests that benzene-benzene interactions maintain their bulk structure in these solutions -that would suggest clustering of the benzenes together, rather than full solubilization by methanol.However figure 5 says that there is only one benzene-benzene interaction in the first solvation shell and thus no evidence of clustering.I'm not sure how these two statements are compatible?Is there evidence of benzene chaining instead?
Author reply: • We are very grateful to the Reviewer for pointing this out.We agree that our comment in the caption to Figure S2 (now Figure S3) "Benzene and methanol maintain their bulk structure in the mixture" is at best confusing, since it might suggest clustering of benzene in the mixture.This, as stated in reference to Figure S5 (now Figure 2a) and elsewhere, is not the case.
In liquid systems the partial radial distribution functions (PRDFs), such as those shown in Figures S2 (now S3) and S5 (now 2), are normalized to 1 at large-r.This definition allows us to compare directly the underlying site-site structure in systems with different molecular number densities, without recourse to rescaling.However, to obtain coordination numbers we need to integrate PRDFs, , according to Equation S5 (was S8).
In the case of benzene-benzene, the first peaks in are strikingly similar in the pure liquid and the benzene-methanol mixture.We have augmented this point to show the benzene-benzene angular radial distribution functions in Figure S5.This analysis indicates that, where present, the benzene-benzene contacts adopt comparable structural motifs in the two cases.However, the coordination numbers differ by more than a factor of ten (12.8 and 1.2 for pure liquid and mixture respectively).This latter value points to a lack of benzene-benzene clustering in the mixture.We don't see evidence for benzene-benzene chaining from the EPSR configurations, and note that in general for chaining we would expect ≥ 2.

Suggested changes to manuscript:
• In the caption for Figure S3 (was Figure S2) we have replaced "Benzene and methanol maintain their bulk structure in the mixture" with "On mixing, changes to the underlying site-site functions of benzene and methanol are relatively subtle".
• We have merged section S1 "Neutron Diffraction Theory" with S5 "Coordination Numbers" so that the complementarity of and are made clear, including the role of number density in the latter.In addition, in this section on page S2 lines 33-36 we have added: "relative probability" "In liquid systems, where there is no long-range order, the in equation S3 therefore have an asymptote of 1 at large-r and give important site-specific structural information of the system." • We have merged Figures S5, S6 and S7 of the SI to give new Figure 2 of the main text.Figure 2a, b and c show the CoM -CoM partial radial distribution functions plotted alongside the coordination numbers for benzene-benzene, methanol-methanol, benzene-methanol in the bulk and in the 1:19 mixture.The benzene-benzene has been added to Figure 2a to highlight the point made by the referee.
• We have added Table 1 to the main text containing the first peak positions, coordination numbers and integration limits corresponding to Figure 2.
• We have added substantial explanatory text regarding benzene-benzene interactions and comparison between pure liquids and the mixture on page 5 lines 81-109: "The lack of low-Q scattering signals in the experimental F(Q)s of Figure 1 is, in itself, a clear indication of the absence of benzene-benzene clustering in the 1:19 methanol solution.To investigate this aspect further, Figure 2 presents the centre-of-mass (CoM) -CoM partial radial distribution functions, gCoM-CoM(r), and coordination numbers, NCoM-CoM(r), for benzene-benzene, methanol-methanol and benzenemethanol interactions (see Supporting Information Section S1 for function definitions).Table 1 provides the corresponding peak positions and the average first shell coordination numbers and their respective integration limits.We note first that in our 1:19 mixture, each benzene molecule is coordinated to an average of 16.4 methanol molecules (Table 1).In contrast to this, we observe only 1.2 benzenebenzene contacts up to an integration limit of 7.8 Å in the mixture, compared to 12.8 in pure liquid benzene.We conclude that in the 1:19 benzene-methanol mixture, the solvation environment around benzene is dominated by interactions with methanol molecules.
Focusing then on Figure 2a, it is interesting to note that while the number of benzene-benzene contacts is reduced by more than a factor 10 in the 1:19 mixture compared to the pure liquid, the position of the first peak in gCoM-CoM(r) is almost unaltered (5.88 Å in the bulk and 5.80 Å in the mixture).This indicates that benzenebenzene contacts adopt comparable structural motifs in the two cases (please see also Supporting Information section S4).The shift of the second benzene-benzene solvation shell to shorter distances (from 10.10 Å in the pure liquid to 9.55 Å in 1:19 methanol solution) indicates that the molecular environment between two secondshell benzenes is constituted by methanol molecules (which are smaller and allow higher packing efficiency) 31 .This observation provides further evidence for benzene solubilization.Figure 2b shows that the CoM methanol-methanol structure is robust to the presence of relatively small amounts of benzene, with the first peak at 4.05 Å shifting to 4.10 Å while the coordination number reduces from 11.0 to 10.0 for pure methanol and 1:19 benzene-methanol respectively.The CoM benzene-methanol radial distribution function exhibits clear first and second solvation shells, with peaks at 5.20 and 8.65 Å (Figure 2c).In addition, there is a shoulder in this function at around 4 Å that points to specific orientation dependent interactions between benzene and methanol.These interactions can be unraveled by interrogating the site-specific correlations that can be extracted by the use of isotopic substitution." • We have added Figure S5 which shows the Angular Radial Distribution Functions (ARDFs) for benzene-benzene neighbours in the bulk liquid and mixture.This figure quantifies the structural similarities and differences in the two cases.
• We have added lines page S10 152 -160: "Figure S5 presents the ARDFs of the relative orientation of the C6 axis of two distinct benzene molecules in bulk benzene and in the 1:19 benzene-methanol mixture.The two ARDFs are similar as they present a first weak peak at 0 ˚ and 180˚, and, at further distances, they show a sharp well-defined peak at 90˚ degrees indicating parallel-displaced and Y displacement respectively.The intensities of the peaks indicate that the benzene-benzene interaction is much weaker in the methanol mixture than in the pure liquid, and this observation is consistent with the information extracted from the partial distribution functions of Figure 2 and the respective benzene-benzene coordination number of 1.2 (Table 1)." 2. Page 5 line 107-108 the authors state "there is no probabilistic preference for 1 rather than 2 hydrogen bonds" however a few sentences previously they say that "the probabilities of 0, 1 and 2 hydrogen bonds are 0.51, 0.41 and 0.08 respectively".This to me suggests that 1-h bond is more probable than 2, so these two sentences appear to contradict each other.Please can the authors clarify what they mean here?